ABSTRACT Synaptic dysfunction represents a core pathological hallmark of Alzheimer's disease (AD). Impairments in synapses underlie changes in the activity of neuronal circuits, which ultimately drive impaired cognition in AD. Despite this, we currently have an incomplete understanding of how and why synapses are altered in AD pathology. If we could advance our understanding of the underlying mechanisms that cause synaptic dysfunction in AD, it would be a significant advancement in the overall understanding of AD. Recent evidence has suggested that pathogenic amyloid beta and tau are enriched in extracellular vesicles and exosomes; but how these vesicles contribute to disease progression, particularly how they affect synaptic function, is still unknown. In preliminary studies, we provide evidence that activation of synaptic NMDA receptors triggers exosome release in neurons, and that this process regulates the level of many synaptic proteins. Importantly, an analysis of these complex datasets using multiple bioinformatic strategies, highlighted key protein-protein interaction networks that are regulated by exosomes including the presence of AMPA receptors, amyloid precursor protein (APP), and tau. Proteomic analysis of purified exosomes from stimulated neurons revealed the presence of several proteins known to cause neurodegeneration, and it suggests that this process may have a major role in the spreading of pathology. Inhibition of exosome synthesis in WT neurons eliminated synaptic potentiation demonstrating a previously unknown function of exosome signaling. Analysis of purified exosomes from the brains of multiple mouse models with AD-like pathology demonstrated an enrichment of APP and amyloid beta peptide as well as an alteration of exosome protein cargos. Based on this evidence, we hypothesize that normal exosome signaling is hijacked by AD pathology contributing to the synaptic dysfunction known to be prevalent in the disease. We propose that activity-induced exosomes, which normally support synaptic strengthening, are overwhelmed by aberrant enrichment of pathogenic molecules which results in disrupted synapses, in particular, impaired synaptic strengthening. We plan to test this hypothesis by combining orthogonal techniques and disciplines including electrophysiological measurement of synaptic function, non-biased proteomic approaches, and imaging of exosome release dynamics. The proposed research has the potential to transform our understanding of how altered activity-induced exosome signaling may contribute to synaptic dysfunction and spreading of AD- like pathology.